Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]2[CH:3]1[CH:4]=[CH:5][C:6]2=[O:8].C1(C)C=CC=CC=1.C([O:25]OO)(C)(C)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>O>[O:25]1[CH:4]2[CH:5]1[C:6](=[O:8])[CH:7]1[CH:3]2[C:2]1([F:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(C)(C)OOO
Reactant: CCOC(=O)C1(F)C2C=CC(=O)C21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(F)C2C(=O)C3OC3C21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16.9 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate was dissolved into 100 ml of toluene. 30.6 ml of 70% t-butylhydroxyperoxide aqueous solution and 11.5 ml of 10% benzyltrimethylammoniumhydroxide/methanol solution were added thereto, and this was stirred at room temperature for 4 hours. After the reaction solution was poured into water, it was extracted twice with ethyl acetate. The obtained organic layers were consolidated to be washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtering off the desiccant, concentration of the filtrate was carried out under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=8:1 to 6:1), yielding 13.4 g of (1RS,3RS,4RS,5SR,6RS)ethyl 3,4-epoxy-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The proton NMR and mass spectrograph data are shown below.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])#[N:19]>>[C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])#[N:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(C#N)c4)nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.072 mMol) 3-cyanobenzoyl chloride, 0.021 gm (92%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=C[C:25]=2[N:24]=[N:23]1.Cl.[CH2:32](N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:23][N:24]([CH3:25])[CH3:32])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Product: CN(C)NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.276 g, 1.0 mmol) in dry DCM (20 mL) were added 231 (0.09 g, 1.5 mmol), 1-hydroxybenzotriazole (0.203 g, 1.5 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.288 g, 1.5 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give 232 (0.25 g, slightly impure) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[CH3:6][C:7]1([CH3:19])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[O:8]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[CH3:3][C:2]([OH:5])([CH3:1])[CH2:4][N:17]1[CH:18]=[C:14]([B:9]2[O:8][C:7]([CH3:19])([CH3:6])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:15]=[N:16]1
Reactant: CC1(C)CO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Isobutylene oxide (101 μL, 1.13 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol) and cesium carbonate (403 mg, 1.24 mmol) stirring in N,N-dimethylformamide (3.4 mL). The mixture was stirred at 80° C. for 16 h, cooled to room temperature, diluted with diethyl ether, washed with water (3×) and brine, dried over sodium sulfate, filtered, and concentrated to give 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (84 mg, 0.31 mmol, 31% yield) as a yellow solid. ESI: [M+H]+ m/z 267.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]2=[N:8][C:7]=1[C:26]([F:29])([F:28])[F:27])=O)C.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[N:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]2[C:6]([CH2:4][OH:3])=[C:7]([C:26]([F:29])([F:28])[F:27])[N:8]=[C:9]12
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2n(-c3ccc(Cl)cc3Cl)c3ccccc3n12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCc1c(C(F)(F)F)nc2n(-c3ccc(Cl)cc3Cl)c3ccccc3n12
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of 8-(2,4-Dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene-3-carboxylic acid ethyl ester (490 mg, 1.11 mmol) in methylene chloride (20 mL), was added at 0° C. a toluene solution of DIBAL-H (5.55 mL, 5.55 mmol). After stirring at 0° C. for 75 min, the reaction mixture was cooled down to −78° C. and methanol (2.2 mL) was added dropwise, followed by additions of ground Na2SO4-10H2O (15.2 g) and celite (2.6 mL). The resulting mixture was warmed up to room temperature in 4 h. After filtration, the solvents were removed in vacuo to afford the title compound as an off white solid (443 mg, 100% yield). 1H NMR (CDCl3, 500 MHz) δ 8.00-7.93 (m, 1H), 7.65 (d, J=2.2 Hz, 1H0, 7.57 (d, J=7.4 Hz, 1H), 7.46 (dd, J=8.6, 2.3 Hz, 1H), 7.37-7.33 (m, 2H), 7.08-7.05 (m, 1H); Mass spec.: 400.02 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH3:28])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8.7 g. of 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester and 1.44 g. of sodium hydride (50% dispersion in oil) in 75 ml. of absolute dimethylformamide was stirred at room temperature for 1 hour and then treated with 4.26 g. of methyl iodide. After stirring at room temperature for 3 hours, the dimethylformamide was removed at 60° C. under vacuum. The residue was dissolved in a mixture of 500 ml. of ethyl acetate and 150 ml. of water. After separation of the phases, the aqueous phase was extracted with 500 ml. of ethyl acetate. The combined ethyl acetate extracts were washed with 300 ml. of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-N-methyl-carbanilic acid ethyl ester having a melting point of 187°-188° C.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[CH:9][N:10]=1)(=O)C>[OH-].[K+]>[NH3:4].[NH2:4][C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][NH:11][C:8]2=[CH:9][N:10]=1
Reactant: CC(=O)Nc1cc2cc[nH]c2cn1
Agent: [K+]
Agent: [OH-]
Product: N
Product: Nc1cc2cc[nH]c2cn1
Yield: 164.8 %

Procedure:
5-Acetylamino-1H-pyrrolo[2,3-c]pyridine (0.61 g, 3.5 mmol) was heated at reflux in methanolic KOH (2M, 15 mL) under nitrogen for 8 hours. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The two layers were separated and the aqueous phase was extracted with n-butanol (3×100 mL). The combined organics were evaporated in vacuo and the residue chromatographed on silica eluting with 5 to 10% MeOH in DCM followed by a gradient of 90:10:1 to 80:20:1, DCM:MeOH:NH3 to give the title compound (0.384 g, 83%) as a red solid. mp 183°-186° C. 1H NMR (360 MHz, d6 -DMSO) δ 4.95 (2H, br s), 6.13-6.15 (1H, m), 6.52 (1H, s), 7.34-7.37 (1H, m), 8.17 (1H, s) and 10.90 (1H, br s).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(C=C)OB([CH:31]=[CH2:32])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([CH:31]=[CH2:32])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 110 °C
Yield: 68.4 %

Procedure:
N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 0.896 mmol) (as in Example 4) and 2,4,6-trivinyl cyclotriboroxane pyridine complex (0.323 g, 1.34 mmol) were dissolved in dioxane (15 mL) and then cesium carbonate (0.584 g, 1.79 mmol) dissolved in water (2 mL) was added. The reaction mixture was degassed with nitrogen for 15 minutes, then tetrakistriphenylphosphine palladium (0.0520 g, 0.0450 mmol) was added and the resulting reaction mixture degassed for 15 minutes. The reaction mixture was then heated to 110° C. for 14 h, allowed to cool, concentrated under reduced pressure and CH2Cl2 (25 mL) was added. The residue was filtered through a CELITE® bed and the filterate dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 3% methanol in chloroform) to yield N-benzyl-5-phenyl-2-vinylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 34.2%). LCMS Condition B-25: retention time 3.12 min, [M+1]=327.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.72 (d, J=5.6 Hz, 2H), 5.60 (d, J=2.4 Hz, J=10.4 Hz, 1H), 6.36-6.56 (m, 3H), 6.72 (d, J=2.8 Hz, 1H), 7.30-7.37 (m, 5H), 7.42-7.52 (m, 5H), 7.74 (d, J=2.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:12]=2)=[O:9])=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[N:3][CH:4]=2)=[O:9])=[CH:12][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)nc2)cc1N1CCN(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)nc2)cc1N1CCN(C)CC1

Procedure:
2-Bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]pyridine-5-carboxamide (0.125 g;0.31 mmol) was stirred with 4-pyridylboronic acid (0.038 g;0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g) and anhydrous sodium carbonate (0.036 g;0.34 mmol) in water (5 ml) and DME (5 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 5%MeOH/CHCl3 to yield a orange/yellow gum(0.060 g;48%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>C(OCC)(=O)C>[Br-:11].[CH2:20]([O:19][P:15]([CH2:14][CH2:13][CH2:12][N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])([O:16][CH2:17][CH3:18])=[O:22])[CH3:21]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: Cc1nc2ccccc2s1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCC[n+]1c(C)sc2ccccc21)OCC
Product: [Br-]
Temperature: 130 °C
Yield: 37.8 %

Procedure:
A mixture of 2-methybenzothiazole (0.36 g, 2.4 mmol) and diethyl (3-bromopropyl)phosphonate (0.67 g, 2.6 mmol) was heated at 130° C. for 4 hrs. After the mixture was cooled to room temperature, ethyl acetate was added. The precipitate formed was collected by centrifugation, washed with ethyl acetate and dried under vacuum to provide Compound 3 (0.37 g). This product was used without further purification. The structure of Compound 3 is given below:
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[S:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:37][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([OH:25])[CH2:23][NH:22][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH:4]4[S:3][C:2](=[NH:1])[NH:6][C:5]4=[O:7])=[CH:10][CH:11]=3)[CH2:16][CH2:17]2)=[CH:31][C:30]=1[NH:32][S:33]([CH3:36])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: N=C1NC(=O)C(Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4SC(=N)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidine-4-one (which was obtained in Example 45) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.50-2.80 (m, 6H), 2.93 (s, 3H), 3.25 (dd, J=14.2, 3.9 Hz, 1H), 3.45-3.60 (m, 2H), 4.40-4.55 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 6.88 (d, J=8.6 Hz, 2H), 6.96 (dd, J=8.3, 2.0 Hz, 1H), 7.04 (d, J=8.6 Hz, 2H), 7.16 (d, J=2.0 Hz, 1H); MS (ES) m/z: 267.7 ((M+2H)2+, 100%), 534.3 (MH+, 45%), 1067.0 (2MH+, 2%); HRMS Calcd. for C24H32N5O5S2 (MH+): 534.1845. Found: 534.1850.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[S:10])[NH2:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.CI.[CH3:15]C(C)=O.CCCCCC>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([S:10][CH3:15])=[NH:9])[CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1cc(C(N)=S)cc(Cl)n1
Reactant: CC(C)=O
Solvent: CI
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(C(=N)SC)cc(Cl)n1
Temperature: 25 °C

Procedure:
In a 100-mL, 3N round-bottomed flask equipped with Thermometer pocket fitted with water condenser, nitrogen inlet and a rubber septum, 2-chloro-6-methoxypyridine-4-carbothioamide (0.58 g, 1.0 eq.), methyl iodide (0.89 mL, 5.0 eq.) was dissolved in diethyl ether (60 mL) resulting reaction mixture was stir at RT. The progress of the reaction was followed by TLC analysis on silica gel with 20% acetone: hexane as mobile phase which shows that starting material was consumed after 15 h. Precipitate was observed that was collected by filtration on Buchner funnel. Solid was separated and compound was collected by filtration on a Buchner funnel and washed with hexane (100 mL); Yield: 0.257 g (41.44%); LCMS (%): 27.07% [M+H]+ 217.92 RT: 4.216 min. (Crude).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:18](=O)[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[O:9][C:10](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].C(Cl)(Cl)[Cl:29]>>[ClH:29].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:10](=[O:11])[C:18]=2[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]1=[O:9]
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: NCCCCCCN
Reactant: ClC(Cl)Cl
Product: Cl
Product: NCCCCCCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Benz[d]indeno[1,2-b]pyran-5,11-dione (4d) (0.100 g, 0.403 mmol) was treated with 1,6-diaminohexane (0.234 g, 2.014 mmol) in CHCl3 (40 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and washed with water (3×25 mL). The solution was dried over sodium sulfate, filtered, and treated with 2 M HCl in Et2O (5 mL). After 30 min, the reaction mixture was filtered and the filter pad was washed with CHCl3 (50 mL) and hexanes (50 mL) to provide an orange solid (0.125 g, 81%): mp 195° C. (dec). IR (film) 3435, 1660, 1630, 1610, and 1504 cm−1; 1H NMR (CDCl3) δ 8.59 (d, J=7.8 Hz, 1H), 8.23 (d, J=8.1 Hz, 1H), 7.85-7.71 (m, 4H), 7.61-7.51 (m, 4H), 4.52 (t, J=7.3 Hz, 2H), 2.78 (m, 2H), 1.79 (m, 2H), 1.59-1.39 (m, 6H); ESIMS m/z (rel intensity) 347 (MH+, 100). Anal. (C22H23ClN2O2.0.5H2O) C, H, N.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[CH2:63][NH2:64].Cl>CN(C=O)C.O>[F:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[CH2:63][NH:64][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: NCc1cccc(F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 4-biphenyl acetic acid (2.00 g, 9.42 mmol) in DMF (20 ml) was added DIEA (3.29 ml, 18.84 mmol) and stirred at room temperature for 15 min, then PyBOP (4.90 g, 9.42 mmol) added and the stirring continued for further 30 min, then 3-fluorobenzylamine (1.18 g, 9.42 mmol) added and the stirring continued for 24 hrs, then the reaction mixture poured on to ice cooled water acidified with (10 ml) 1 N HCl and extracted with ethyl acetate (100 ml) and the organic layer washed with saturated solution of NaHCO3, water and brine, dried over Na2SO4 and the solvent removed under vacuum to give a white powder of the desired compound (1.00 g) 33% yield. Another method involves the acid chloride coupling method described below.
Reaction SMILES: [C:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:15][OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1nccs1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C(c1ccccc1)c1nccs1
Temperature: 25 °C

Procedure:
To Phenyl-thiazol-2-yl-methanone (0.5 g) in ethanol (6 mL) was added hydroxylamine hydrochloride (3 eq) and sodiumcarbonate (3 eq). The reaction mixture was stirred at reflux overnight and then allowed to cool down to room temperature. The precipitate was then isolated by filtration and washed with water to yield the title compound as a light grey solid. MS (m/e): 207.1 (5), 206.1 (10), 205.1 (100% M+H+)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:19])[C:10]=1[CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:19][C:9]1[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=1
Reactant: [N-]=[N+]=NCc1cncc(Cl)c1COC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cncc(Cl)c1COC1CCCCO1

Procedure:
A solution of 3-azidomethyl-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.46 g, 1.6 mmol) and triphenylphosphine (0.43 g, 1.6 mmol) in THF (15 mL) and H2O (0.15 mL) was stirred at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaHCO3 solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 256.8 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31].C(N(CC)CC)C.Cl.[CH3:43][S:44][CH2:45][CH2:46][NH2:47].ClCCl>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH2:27][NH:47][CH2:46][CH2:45][S:44][CH3:43])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:31]
Reactant: CSCCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CSCCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reaction time: 0.17 h
Yield: 56 %

Procedure:
10.0 g of compound 5-(4-(4-(3-fluorobenzyloxy)-3-chloroanilino)-6-quinazolinyl)furan-2-formaldehyde was dissolved in the mixture of dichloromethane/methanol (3:1). The mixture was added with 4.3 g of triethylamine, stirred for 10 min, added with 6.9 g of 2-methylthioethylamine hydrochloride, and stirred at room temperature. Upon consumption of the starting materials detected by TLC, 2.4 g of sodium borohydride was added in batches under ice-bath. Upon the end of reaction detected by TLC, dichloromethane (q.s.) was added. The mixture was washed with saturated ammonium chloride and then with saturated sodium chloride, dried over anhydrous sodium sulfate, and subjected to a column chromatography to obtain 6.5 g of yellow solid, yield 56%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCCC(=O)O
Product: CCCC(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and n-butyric acid as starting materials, MS (LC/MS): 373.2 (M+H).